Adult hepatocytes generally remain quiescent and rarely undergo cell division, but retain the ability to undergo cell division and proliferation in response to acute and chronic injury or loss of liver mass after hepatic resection. Despite intense investigations for the past several decades, the molecular identity of humoral factors associated with hepatic resection, which serve as the initial trigger for the cell cycle entry of otherwise quiescent adult hepatocytes are not well understood. In recent years, extracellular ATP is emerging as an important signaling molecule influencing a variety of liver functions via the activation of cell surface P2 purinergic receptors, and the mitogenic potential of extracellular purines are beginning to be recognized in many other cell types. However, the role of purinergic signaling in hepatocyte proliferation and liver growth remains largely unexplored. Therefore we hypothesize that extracellular purines via the activation of P2 purinergic receptors activate cell cycle progression and proliferation of adult hepatocytes. The Specific Aims (SA) of this proposal are designed to test this overall hypothesis in appropriate in vitro and in vivo experimental models SA1. To examine the molecular mechanisms of P2 purinergic receptor mediated cell cycle progression and proliferation of hepatocytes in vitro. SA2. To determine if the mitogenic effects of extracellular purines are dependent on c-Jun N-terminal Kinase (JNK) signaling. SA3.To characterize the molecular mechanisms of P2 purinergic receptor mediated activation of JNK signaling in hepatocytes. SA4. To determine the mitogenic effects of extracellular purines on hepatocyte proliferation and liver growth in vivo. The knowledge gained by these studies will significantly advance our understanding of the role of extracellular purines in hepatocyte cell cycle control and reveal potential new targets within the liver with implications for better management of multiple liver disorders, especially impaired liver regeneration after hepatic resection associated with chronic liver diseases. D